Suppressing synchronous firing of epileptiform activity by high‐frequency stimulation of afferent fibers in rat hippocampus

Abstract

Aims Deep brain stimulation (DBS) is a promising technology for treating epilepsy. However, the efficacy and underlying mechanisms of the high‐frequency stimulation (HFS) utilized by DBS to suppress epilepsy remain uncertain. Previous studies have shown that HFS can desynchronize the firing of neurons. In this study, we investigated whether the desynchronization effects of HFS can suppress epileptiform events. Methods HFS trains with seconds of duration (short) and a minute of duration (long) were applied at the afferent fibers (ie, Schaffer collaterals) of the hippocampal CA1 region in anesthetized rats in vivo. The amplitude and the rate of population spikes (PS) appeared in the downstream of stimulation were calculated to evaluate the intensity of synchronized firing of neuronal populations between short and long HFS groups. A test of paired‐pulse depression (PPD) was used to assess the alteration of inhibitory neuronal circuits. Results The sustained stimulation of a 60‐s long HFS suppressed the afterdischarges that were induced by a 5‐s short HFS to impair the local inhibitions. During the sustained HFS, the mean PS amplitude reduced significantly and the burst firing decreased, while the amount of neuronal firing did not change significantly. The paired‐pulse tests showed that with a similar baseline level of small PS2/PS1 ratio indicating a strong PPD, the 5‐s HFS increased the PS2/PS1 ratio to a value that was significantly greater than the corresponding ratio during sustained HFS, indicating that the PPD impaired by a short HFS may be restored by a sustained HFS. Conclusions The sustained HFS can desynchronize the population firing of epileptiform activity and accelerate a recovery of inhibitions to create a balance between the excitation and the inhibition of local neuronal circuits. The study provides new clues for further understanding the mechanism of DBS and for advancing the clinical application of DBS in treating epilepsy.

An Anodic Phase Can Facilitate Rather Than Weaken a Cathodic Phase to Activate Neurons in Biphasic-Pulse Axonal Stimulations

“…The positions of electrodes were kept fixed throughout the period of data collection. After the animal experiments, the correction of electrode positions was confirmed by a histology analysis of brain slices ( Wang et al, 2021 ).…”

In vivo inhibition of epileptiform afterdischarges in rat hippocampus by light‐activated chloride channel, stGtACR2

“…For example, optogenetic inhibition of principal excitatory CA3 neurons using Jaws in the PP kindling model significantly reduced afterdischarge duration and behavioral severity 31 . Additionally, in an anesthetized rat model of afterdischarge (SC stimulation), high‐frequency electrical stimulation of the SC prevented afterdischarge propagation to the CA1 subfield by desynchronizing neurons from epileptiform activity 47 . Several studies have indicated the potent seizure‐suppressing effects of activating GABAergic interneurons (i.e., indirectly inhibiting excitatory neurons) in various preclinical models.…”

“… 31 Additionally, in an anesthetized rat model of afterdischarge (SC stimulation), high‐frequency electrical stimulation of the SC prevented afterdischarge propagation to the CA1 subfield by desynchronizing neurons from epileptiform activity. 47 Several studies have indicated the potent seizure‐suppressing effects of activating GABAergic interneurons (i.e., indirectly inhibiting excitatory neurons) in various preclinical models. However, depending on the interneuronal axonal projections, such an optogenetic inhibitory approach can affect larger volumes of the brain beyond the illuminated site.…”

Cathodic- and anodic-pulses can alternately activate different sub-populations of neurons during sustained high-frequency stimulation of axons in rat hippocampus

“…Then the SE was inserted gradually to approach the alveus until the amplitude of APS evoked by a test cathodicpulse (100 µs, 0.3 or 0.4 mA) was not able to increase further, indicating that the inner pole of SE had reached the alveus. After the experiments, the electrode positions were confirmed by stained sections (figure 1(A, right)) of paraformaldehyde-fixed brains by histological methods reported previously [28].…”